Our long-term goal in this project is to define a novel mechanism by which cancer cells evade NK cell detection that can be targeted to improve current cancer therapies. Acute myeloid leukemia (AML) is one of the most common types of leukemia that is particularly dangerous in the elderly population, where the 5 year survival is less-than 10%. Despite our best efforts for the past 50 years, clinical outcomes remain largely unchanged, which is especially despairing for the many patients who are awaiting breakthroughs in translational research. Natural killer (NK) cells represent an encouraging frontier for novel anti-cancer treatments as they have the innate ability to identify, target, and lyse cancer cells without prior sensitization. Accumulating evidence supports the notion that cancer cells can negatively impact immune cells, including NK cells. We believe at least part of this negative regulation is due to cancer-derived signals which activate the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor expressed in immature developing NK cells, which has been shown to alter NK cell maturation. Therefore, we hypothesize that activated AHR can repress NK cell maturation by upregulating microRNAs which target key transcription factors important for promoting the final stages of NK cell development. Furthermore we hypothesize that AML cells release soluble agonists which utilize this pathway to disrupt NK cell differentiation and promote cancer progression. Thus our aims are 1) To identify and characterize the mechanism by which AHR regulates human NK cell differentiation and 2) to interrogate the cancer driven immune-modulatory strategies targeting NK cells through AHR. As part of these studies we will also test the clinical efficacy of using a pharmacological AHR antagonist in vivo to promote the number of mature and functional NK cells capable of killing cancer cells. This project is an important approach to cancer immunology because it combines both mechanistic studies to improve our understanding of the pathogenesis of cancer, as well as provides impactful preclinical studies which are aimed to override these inhibitory pathways.